The sequence of a stepwise AdE reaction and ... - ACS Publications

J. Am. Chem. SOC.1992, 114, 5555-5566

5555

The Sequence of a Stepwise AdE Reaction and Intramolecular Pauson-Khand Cycloaddition as an Entry into the Synthesis of Polycyclic Compounds A. S. Cybin,t**W. A. Smit,*pt,t R. Caple,**l A. L. Veretenov,+A. S. Shashkov,t L. C.Vorontsova,+M. G.Kurella,+V. S. Chertkov,g A. A. Carapetyan,lI A. Y. Kosnikov,ll M. S. Alexanyan,"S. V. Lindeman,"V. N. Panov,lI A. V. Maleev,ll Y. T. Struchkov,ll and S. M. Sharpel Contribution from the Zelinsky Institute of Organic Chemistry, Academy of Sciences USSR, Leninsky Prospect 47, Moscow, USSR, I I7913, Chemical Department of Moscow State University, Moscow, USSR, 11 7234, Laboratory of X-ray Structural Studies, Nesmeyanov Institute of Organoelement Compounds, Academy of Sciences USSR, Vavilova Street 16, Moscow, USSR, 117813, and Chemistry Department, University of Minnesota-Duluth, Duluth, Minnesota 55812. Received December 16, I991 Abstract: A stepwise AdEacylmethoxylationacross the double bond of dicobalt hexacarbonyl complexes (DCHCC) of conjugated enynes was elaborated as an efficient and general route for the synthesis of DCHCC of 1,6-enynes containing a combination of five- and six-membered-ring fragments. Depending on the structure of these adducts, the latter either were subjected to 1,2-carbnyl reduction followed by an intramolecular Pauson-Khand (IMPK) cyclization or were directly utilized as substrates for this process. A list of model polycyclic systems which were assembled using this approach includes [5.5.5] angularly fused compounds, [6.5.5] and [5.5.5] linearly fused tricyclics, and linearly and angularly fused [6.5.5.5] and [5.5.5.5] tetracyclic products. A novel convergent and general method for the synthesis of various cyclic compounds is suggested on the basis of the AdE-IMPK tandem sequence as the key steps for the assemblage of polycyclic frameworks. This option seems to be especially promising for the tetracyclic derivatives mentioned above, as in these cases only two operationally simple steps are required to convert read:'-/ available starting blocks into the target structures related to natural polyquinanes.

Introduction We have shown in previous studies that the AdE reaction across the double bond of a dicobalt hexacarbonyl complex (DCHCC) of conjugated enynes could be carried out in a stepwise manner as a real sequence of independent additions of an electrophile and a nucleophile via the formation of a stabilized carbocationoid intermediate (CCI).lBqb Since the nature of both the electrophile and nucleophile can be varied independently and over a broad range, this reaction is applicable as a general method of regiospacific 1,2-functionalization of conjugated enyneslcdin accordance E = ArS, NO2. tert.-Alkyl, Acyl with the general equation represented in Scheme I. Nu = OH, OAlkyl, OAlkenyl, TMS vinyl ethers, Allyl silanes The utilization of unsaturated electrophile and/or nucleophiles as the addends in this reaction opened the entry into an easy Scheme 11" preparation of variously substituted enynes from simple building blocks.2a* Specifically, it was shown that this AdE route could serve as a short and flexible method for the synthesis of DCHCC of 1,6-enynes, valuable precursors for the intramolecular Pauson-Khand (IMPK) cyclization ([2 2 l ] c y c l ~ a d d i t i o n ) . ~ ~ ~ ~ Thus the sequence, AdE reaction followed by IMPK cyclization, was developad as a short and convergent protocol for the synthesis of a series of bicyclo[3.3.3]octenones4s" and their 3-oxa anal o g ~ , *as~ is * ~illustrated ~ in Scheme II.48 Among the options given in Scheme 11, the former, based on the use of unsaturated acylium ions, was shown to be the most promising due to the ease of preparation and handling of these species belonging to various structural types.2avC,d The present study was initiated with the aim of testing the applicability of the suggested methodology to a more complicated l.M' task, namely, to the synthesis of angularly and linearly fused 2 . & a +h212tll-Oi_t_,o / polycyclic systemsSwhich are related to the natural polyquinanesP H

+ +

qk

Results and Discussion Angularly Fused Tricyclics. The synthesis of angularly fused compounds along a route similar to that outlined in Scheme I1 implied the use of a cyclic acyl cation as an electrophile in the AdE reaction. The interaction of DCHCC of vinylacetylene 1 with Zelinsky Institute of Organic Chemistry. ton leave from Zelinsky Institute. Moscow State University. 1' Nesmeyanov Institute of Organoelement Compounds. University of Minnesota-Duluth.

OThroughout this paper M = Co2(CO),; Y = BF4. 1-cyclopentenoyl tetrafluoroborate 2 (the latter, as well as other acylium salts used in this study, was generated in situ via the (1) (a) Schegolev, A. A.; Smit, W. A.; Kalyan, Y. B.; Krimer, M. 2.; Caple, R. Tetrahedron Lett. 1982, 23, 4419. (b) Schegolev, A. A,; Smit, W. A.; Mikaelyan, G. S.; Gybin, A. S.; Kalyan, Y. B.; Krimer, M. 2.; Caple, R. Izu. Akad. Nauk SSSR,Ser. Khim. 1984, 2571. (c) Mikaelian, G. S.; Gybin, A. S.;Smit, W. A,; Caple, R. Tetrahedron Lett. 1985, 26, 1269. (d) Mikaelyan, G. S.; Gybin, A. S.;Smit, W. A. Izu. Akad. Nauk SSSR,ser. Khim. 1985, 2277.

0002-7863/92/1514-5555%03.00/0 0 1992 American Chemical Society

5556 J . Am. Chem. SOC.,Vol. 114, No. 14, 1992

Gybin et al.

Table I. 'H NMR Data for 5a-d" H-6 H-4 H-3 H-3 H-2 H-8 Me0 others 2.28, ddd 4.13, d 4.49, dd 2.48, dd 2.77, d 3.40, s Sa 6.16, s 1.6-1.9, m (7.2, 5.0) (15.0, 7.2) (1 5.0, 5.0, 4.5) (4.5) (8.5) 4.22, t 2.28, ddd 2.16, ddd 2.52, d 3.41, s 1.6-2.1, m 5b 6.06, d 4.65, ddd (1.85) (9.5, 3.1, 1.85) (17.0, 9.0, 3.1) (17.0, 9.5, 9.0) (9.0) (8.5) 2.49, ddd 1.94, ddd 3.95, dd 2.71, m 3.33, s 1.2-2.3, m 5c 6.05, s 4.27, dd (7.5, 5.2) (13.5, 7.7, 7.5) (13.5, 10.0, 5.2) (10.0, 7.7) 2.65, ddd 2.01, dd 4.0, d 2.86, dd 5d 6.17, d 4.62, ddd 3.46, s 1.4-2.0, m (1.9) (9.2, 2.4, 1.9) (15.0, 9.2, 4.7) (15.0, 2.4) (4.7) (8.5, 1.5) "The IH N M R data were taken a t 250 MHz in CDCI, with T M S as internal standard. J values are given in hertz in parentheses. Table 11. 13CN M R Data for 5a-d"

c-7 c-5 183.6 5s 214.8 183.2 5b 213.3 182.9 5c 214.0 187.8 5d 213.6 "The "C N M R data were taken a t

C-6 c-2 c-4 c-1 C-8 76.0 75.2 66.4 53.2 128.5 76.7 73.6 64.2 57.0 126.1 75.5 73.3 64.9 57.5 130.0 77.9 75.6 66.5 52.9 126.8 75 MHz in CDCI, with T M S as internal standard.

interaction of the respective acyl fluoride with gaseous BF3) under the previously described conditions of methoxyacylationZa proceeded with an amazing efficiency and gave the expected adduct 3 in nearly quantitative yield (Scheme 111). As was shown earlier,3b*4b,c DCHCC of 1,6-enynes bearing a carbonyl group in conjugation with the double bond, which are formed as the immediate products of AdE acylation of DCHCC of 1,3-enynes, are unable to undergo the IMPK reaction (see, however, data presented below in Schemes XII-XIV), Hence, additional manipulations of these adducts were required to transform the latter into suitable substrates for IMPK cyclization. Both 1,2-Grignard addition4band hydride reduction"qd were previously used to achieve this goal. For the adduct 3, hydride reduction in a NaBH,CeCl,-MeOH system (cf., data in ref 4d) proved to be very efficient, and the respective hydroxy product 4a,b was obtained as a mixture of easily separable (TLC) diastereomers in excellent total yield. Attempts to perform the IMPK reaction with these substrates under conventional conditions by thermolysis in solution (liquid phase conditions, LPC, hexane, 80 OC, several hours, sealed vessel; compare with the data given in ref 3) were rather fruitless since only trace amounts of the metal-free polar compound, supposedly of the expected cycloadduct type, were detected. On the contrary, under the previously elaborated dry state adsorption conditions (DSAC7aT),the cyclization of both isomers 4a and 4b (2) (a) Smit, W. A.; Schegolev, A. A.; Gybin, A. S.; Mikaelyan, G. S.; Caple, R. Synthesis 1984, 887. (b) Smit, W. A.; Simonyan, S. 0.;Mikaelyan, G. S.;Mamyan, S. S.; Gybin, A. S.; Shashkov, A. S.; Caple, R. Izo. Akad. Nauk SSSR, Ser. Khim. 1989, 334. (c) Mikaelyan, G. S.; Smit, W. A,; Batsanov, A. S.;Struchkov, Y. T. Izu. Akad. Nauk SSSR, Ser. Khim. 1984, 2105. (3) (a) The IMKP reaction was originally described in the following: Knudsen, M. J.; Schore, N. E. J . J . Org. Chem. 1984, 49, 5025. (b) For a general review of the reaction, see: Schore, N. E. J. The Pauson-Khand Cycloaddition Reaction for Synthesis of Cyclopentenones. In Organic Reacfions; Paquette, L. A,, Ed.; Wiley: New York, 1991; Vol. 40, p 2. (4) (a) General approach is outlined in the following: Caple, R. Utilization of Stepwise AdE Reactions in Designing Organic Synthesis. In Organic Synthesis: Modern Trends; Chizov, O., Ed.; Blackwell Scientific Publications: Oxford, UK, 1987. See also: (b) Smit, W. A.; Gybin, A. S.; Shashkov, A. S.; Struchkov, Y. T.; Kuz'mina, L. G.; Mikaelian, G. S.;Caple, R.; Swanson, E. D. Tefrahedron Left. 1986, 27, 1241. (c) Gybin, A. S.; Smit, W. A,; Veretenov, A. L.; Simonian, S. 0.; Shashkov, A. S.; Struchkov, Y. T.; Kuz'mina, L. G.; Caple, R. Izu. Akad. Nauk SSSR, Ser. Khim. 1989, 2756. (d) Veretenov, A. L.; Gybin, A. S.; Smit, W. A,; Chertkov, V. A,; Shashkov, A. S. Izu. Akad. Nauk SSSR, Ser. Khim. 1989, 1879. (5) For a preliminary communication, see: Smit, W. A,; Gybin, A. S.; Simonian, S. 0.;Veretenov, A. L.; Shashkov, A. S. Izo. Akad. Nauk SSSR, Ser. Khim. 1987, 232. (6) (a) Paquette, L. A. Top. Curr. Chem. 1984, 219, 1. (b) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41. (7) (a) Simonyan, S. 0.;Smit, W. A,; Gybin, A. S.; Shashkov, A. S.; Mikaelian, G. S.;Tarasov, V. A.; Ibragimov, I. I.; Caple, R.; Froen, D. E. Tetrahedron Lett. 1986,27, 1245. (b) Smit, W. A,; Simonyan, S. 0.;Tarasov, V. A.; Mikaelian, G. S.; Gybin, A. S.; Ibragimov, I. I.; Caple, R.; Froen, D. E.; Kreager, A. Synthesis 1989, 472. (c) Smit, W. A.; Simonian, S. 0.; Tarasov, V. A.; Shashkov, A. S.; Mamyan, S. S.; Gybin, A. S.;Ibragimov, I. Izu. Akad. Nauk SSSR. Ser. Khim. 1988, 2796.

C-9-11

c-3 44.0 40.2 42.3 41.6

34.7 29.0 29.3 34.8

29.1 27.4 26.8 28.6

Me0 57.4 57.9 56.4 58.0

25.2 23.4 24.6 25.2

Scheme 111

4k

&3

a :b

=

1.5 : 1

OW? SIO,,

IOO'C,

4a

'J

l h , 41%

&

59

54 a:b=3 : 5

P" SIO2. 100QC

*

4.b I h , 30%

5s

5.d c : d = 1.1 : 1

proceeded smoothly, albeit with a lower efficiency* than that reported for simpler m ~ d e l ~ . ~ ~ ~ * ~ ~ ~ Both reactions were nonstereospecific and led to the formation of stereoisomeric mixtures of the tricyclic products, 5a,b and 5c,d, respectively, (Scheme 111) which were separated by TLC. The structure of adduct 5a was shown by X-ray analysis to be

(1R*,2S*,4S*,8R*)-4-methoxy-2-hydroxytricycl0[6.3.O.O'~~]undec-5-en-7-one. These data also unequivocally proved the configuration of the adduct 4a used to prepare 58. Since both Sa and 5b originate from the same isomer 4a, these products must have the same relative anti configuration of hydroxy and methoxy groups and, hence, can differ only by the stereochemistry of the ring junction at C-1 and C-8. Products 5c and 5d formed from 4b are expected to have syn-oriented M e 0 and HO substituents. Their structures were ascertained from the comparison of 'H N M R spectral patterns of 5a-d (Table I) and the observation of NOES in their ' H N M R spectra. In fact, a strong NOE was observed for protons at C-2 and C-1 1 only for Sa and 5d, while 5b and 5c exhibited an NOE between protons a t C-2 and C-8. (8) No yield optimization was tried. Most low yields were usually due to noticeable (TLC) decomplexation of the initial substrates.

Stepwise Ad, and Intramolecular Pauson-Khand Reactions Scheme IV

J . Am. Chem. SOC.,Vol. 114, No. 14, 1992 5557 Scheme V

6

&

P

b

52%

0 92% R=H, 1p

LAC,=

91%

m

95%

93%

95% a'b=9:1

a :b = 12.1

m - E 87% a : b . c = 9 : 1.6 : 1

R=H, 12a,

R=H 129

87% a b = 3 8 1 R-Ac,

13a

R=Ac,

73%. a b = 3 3

jJ.b

1

Analysis of the spin-spin coupling of the proton at C-6 also provided useful criteria for the stereochemical assignments. In fact, previous data for a series of substituted bicyclo[3.3.0]0~y y h LPC 50% 10h 70% 21a 2 1 b = 1 1 tenones revealed that the proton a t C-6 appeared as a singlet in on D S A C 5 5 % 4h 65% a m= 2 1 'H N M R spectra of the diastereoisomers with an endo orientation of the proton a t C-4, while a doublet with J4 = 1.8-2.0 was reaction under DSAC led to the formation of the tricyclic adduct, observed in IH N M R spectra of isomers having an exo proton 1O-methyl-8-hydroxy(or acetoxy)-2-methoxytricyclo[7.3.0.02 7]at C-4."qd A similar pattern of splitting was observed for the pairs dodec-l( 12)-en-ll-one 12 (or 13) in good yield. In both cases, 5a,c (H-6, singlets) and 5b,d (H-6, doublets) (see Table I). the conversion proceeded in a stereoselective manner, giving as The nonstereospecificity of the 4 5 conversion closely parmajor products stereoisomers 12a or 1%. Cyclization of 1Oa under alleled the observations reported earlier by Neil Shore's group LPC proceeded with a lower efficiency as compared with DSAC; concerning the steric course of the IMPK reaction which had been adduct 12 was formed in 39% yield after heating the substrate used for the synthesis of angularly fused triquinanes with a difin hexane at 60 OC for several hours (TLC data indicated the ferent pattern of s u b s t i t u t i ~ n . ~It~is*also ~ ~ ~worthwhile ~ to note complete conversion of the starting material). that the results of our previous studies on the steric course of the The 2R*,7S*,8R* configuration for diastereomers 12a,b (or formation of the bicyclo[3.3.0] system from 1,6-enynes bearing substituents both at the allylic and propargylic ~ i t e ~ also ~ ~ , ~13a,b) ~ * follows from the configuration of the corresponding centers in the starting material 10 (or 11). Relative configurations at attest to a rather low stereoselectivity in cycloadditions for the C-9 and C-10 in 12a (or 13a), as represented in Scheme IV, were polysubstituted substrates in the absence of a discriminating bulky established from the observation of NOES in 'H N M R spectra substituent. of 13a and 13b." Linearly Fused Tricyclics. The suggested tandem sequence of Acylation of 6 with acryloyl tetrafluoroborate 14 proceeded AdE plus IMPK reactions can be applied to the synthesis of the in a more complicated manner, and the yield of the desired acyl title system^,^ provided DCHCC of cycloalkenylacetylenes are methoxy adduct I5 never exceeded 24% despite all attempts to used as starting materials. secure better results by modifications in the reaction conditions.I2 We have found that this route is especially useful for the Hence, an alternative route was devised based upon the use of synthesis of the [6.5.5] framework from DCHCC of l-ethynyl3-chloropropionyl tetrafluoroborate 17 as a masked equivalent cyclohexene 6. Thus, methoxyacylation of the latter compound of 14. Reaction of 6 with 17 under standard conditions gave with crotonoyl tetrafluoroborate 72aproceeded readily and gave adducts 18a,b as a mixture of stereoisomers in nearly quantitative the desired trans adduct 8 with the E configuration of the double yield. Oxidative decomplexation of this mixture produced 19a,b bond in a satisfactory yieldlo (Scheme IV). (a:b = 9:l). The latter, when applied to the surface of A l a 3 Unfortunately, attempts to achieve direct reduction of the (basic), underwent smooth dehydrochlorination,13accompanied carbonyl group in 8 under the conditions successfully used for 3 by a partial isomerization, and yielded enones 16a,b enriched with failed. To circumvent this problem, adduct 8 was converted into the major isomer 16a. Hydride reduction of 16a,b proceeded the decomplexed ketone 9 (upon treatment with cerium(1V) amsmoothly and gave allyl alcohol 20 as a mixture of three isomers monium nitrate), and the latter was smoothly reduced into the (Scheme V). The major component, 20a was isolated in 67% respective allyl alcohol 10 (a single stereoisomer was formed), yield. Treatment of 2Oa with Co2(CO), followed by IMKP rewhich was further transformed into the acetate 11 (Scheme IV). action produced the tricyclic enones 21a,b as a mixture of two Single-crystal X-ray analysis of the latter established its structure isomers in a good total yield. as (1R*,2RS,1'R*)- 1-methoxy- 1-ethynyl-2- [ ( E ) -1'-acetoxybut2'-enyl]cyclohexane. (1 1) The stereochemistry shown was additionally ascertained from the Treatment of 10 (or 11) with C O ~ ( C Ofollowed )~ by the IMPK

-

(9) (a) Schore, N. E.; Knudsen, M. J . J . Org. Chem. 1987, 52, 569. (b) Schore, N. E.; Rowley, E. G. J . Am. Chem. SOC.1988, 110, 5224. (10) Adduct 8 was formed as a mixture of E and Z isomer configurations of the double bond (total yield 65%, ratio 5 1 ) . Formation of the latter isomer is obviously due to partial isomerization of the reacting acylium cation 7 since the starting acyl fluoride contains ca. 5% Z isomers ('HNMR). Only the E isomer was used in further reactions. The same refers to the preparation of adduct 29 (vide infra).

analysis of the splitting pattern for vicinal JiH7iH and J13c-i~ in comparison with earlier data for the series of substituted bicycl0[3.3.0]octenone derivatives.4E.d A detailed dixussion of these data will be published separately. (12) TLC monitoring revealed that the reaction of 6 with 14 proceeded quite cleanly. The low yields of 15 are obviously due to the increased propensity of this adduct to undergo polymerization under the conditions of its isolation and purification (cf. data in ref 4d). (13) This dehydrochlorination procedure was elaborated earlier as the method of choice for similar adducts prepared by the acylation of acyclic enynes.&

5558 J . Am. Chem. SOC.,Vol. 114, No. 14, 1992 Table 111. ' H NMR Data H-12 13a 6.02 d 13b 5.92 d 2la 6.04 d 2lb 5.94 d 27s 5.95 S

27c

5.86 S

Gybin et al.

for Substituted Tricyclo[7.3.0.02~7]dodec-l(12)-en-l 1-ones (250 MHz, CDC13)" H-8 OMe H-9 H-lOn H-lox H-7 Me 4.44 3.19 2.76 2.35 2.23 1.22 ddd d dd S dddd dq 5.21 3.32 2.98 2.27 2.3 1.12 dd S ddd m m d 3.50 3.25 3.13 2.23 2.88 2.12 m S dddd dd dd m 4.10 3.28 3.25 2.62 2.37 2.13 m S m dd dd dd 3.49 3.20 2.33 2.43 2.25 ... 1.31 d d ddd S d S 4.00 3.14 2.79 2.05 2.44 1.28 d S d d m S 3.20 2.28 2.57 1.53 1.31 ... 3.88 m S d d dd S 3.92 3.09 2.84 2.07 1.29 1.35 d S d d m S

H-3-H-6 H-6n 0.85, m, 1.2-2.2, m 1.2-2.0, m H - ~ xn, 0.8, m, 1.1-1.9, m 1.2-2.0, m H-6x 1.86, m H-6n 1.19, m, 1.3-1.8, m 1.2-2.0, m

H-3x 2.37, dt H-3n 1.23, m, 1.2-1.9, m 27f 5.77 H-3x 2.29, dt S H-3n 1.24, m H-6x 1.27, m H-6n 1.73, m, 1.1-1.8, m a In the spectra of 13a and 13b the protons of the Ac group appears as singlets at 2.07 and 2.04 ppm, respectively. Coupling constants (Hz): J7,8 = 3.0 (13a), 7.4 (13b), 3.7 ( 2 1 4 , 5.4 (21b), 7.0 (27a), 5.5 (27c), 6.0 (27d), 9.0 (270; J 8 , 9 = 5.2 (13a), 9.2 (13b), 1.6 ( 2 1 4 , 7.5 (2lb); J9,1oX = 7.0 (Zla), 7.8 (21b); J9,10n = 4.2 (13a). 4.3 (13b), 4.2 (21a), 3.7 (21b); J1Ox,lOn = 16.2-18.2 for all compounds; J9.12 = 2.3-2.5 for 13a,b and 21a,b; J7,9 = 1.1 (13a) and 0 (13b); J8.O" = 12.1 (for 27f only!). 27d

5.81

S

Table IV. 13C NMR Data for 13a,b and 27a,c,d,f (75 MHz, CDC13, TMS)"

C-11 C-1 C-12 13a 210.9 127.4 181.1 121.6 13b 209.7 184.6 270 209.3 188.1 128.1 127.2 27c 211.3 189.3 124.1 27d 209.2 192.4 123.8 27f 211.3 191.8 "Signals of the CH3CO0 group present

C-8 C-2 C-9 C-7 Me0 50.9 80.6 57.3 52.1 77.3 51.4 72.0 51.7 47.6 77.3 51.7 54.6 80.9 80.5 52.4 52.0 51.5 76.4 80.5 54.0 53.8 52.4 77.4 82.8 52.9 52.1 79.6 52.1 58.6 81.5 in 13a and 13b appear at 170.9 and 21.2 ppm

In this case, the IMKP reaction proceeded with comparable ease both under LPC and DSAC. However, in the latter case, a slightly higher stereoselectivity was observed. Products 21a and 21b were separated by TLC. Their structures (and hence the stereochemistry of the precursor 2Oa) were ascertained from the observation of NOEs in 'H N M R spectra and by comparison of the latter with the respective data for 12a,b" (Table 111). A direct acylation of 6 with methacryloyl tetrafluoroborate was also found to be unsuitable as a preparative method due to the low yield and instability of the product under the reaction conditions and/or product isolation. By analogy with the above mentioned precedent this problem was solved by the use of 2methyl-3-chloropropionyl tetrafluoroborate 22 as an acylating agent. The corresponding adduct 23 was prepared in nearly quantitative yield (Scheme VI). Further decomplexation into 24 (mixture of four isomers in the ratio 3:2:1:1, IH N M R data) and dehydrochlorination of the latter over A1203 resulted in formation of the methacryloyl methoxy adduct 25a,b in an excellent overall yield. It was rather surprising to find out that the sequence of reactions leading from 6 to 25 produced, predominantly, isomer 2% with a cis orientation of the acyl and methoxy groups, while a similar sequence applied to the preparation of an acryloyl analog gave, as the major product, 16a with a trans configuration of these groups (cf. data in Schemes V and VI). Individual products 25a and 25b were further reduced under standard conditions into the corresponding allyl alcohols 26a,b and 26c,d. In both cases, 1,2-carbonyl reduction proceeded as a stereoselective process (Scheme VI). The stereochemistry of 26a-d as well as that of the starting ketones 25a,b was inferred from the data on the structure of the final tricyclic products derived therefrom (vide infra). Upon treatment with C O ~ ( C O )26a-d ~ , were converted into the corresponding DCHCCs. IMPK cyclization of these complexes turned out to be a fairly efficient process under both LPC and DSAC. The stereochemistry varied from high selectivity (for %,c) to complete specificity (for 26b,d). It should be noted again that the cyclization of 26c under DSAC revealed higher selectivity as compared with LPC (Scheme VII). The structure of the

C-34-6 C-10 50.4 28.5 28.0 23.4 22.0 44.4 29.0 22.0 20.1 18.9 53.1 27.2 24.6 20.4 18.9 47.1 26.7 20.9 20.9 18.6 25.4 21.7 56.0 27.3 20.3 49.0 27.3 25.6 23.5 20.3 (for 13a) and 170.2 and 21.2 ppm (for 13b).

Me 14.0 14.0 21.5 26.3 24.4 29.3

Scheme VI M

a 2a

a W

94%

96%

a : b : c : d = 3 : 2 : 1: 1

AI,O,,

24d

r.t., 30 min

-[HCI]

233

CI

b 74%

25%

-&

20%

60%

2.M

&I 15%

tricyclic adducts as stereoisomers of 9-methyl-8-hydroxy-2methoxytricyclo[7.3.0.02~7]dodec-l (12)-en-ll-ones 27a,c,d,f (minor isomers 27b,e have not been isolated in a pure state) was deduced from the observation of NOEs in their IH N M R spectra and by comparison of the patterns of 'H and I3C N M R spectra of these products with the data for the above mentioned linearly fused tricyclic products" (Tables I11 and IV). The successful synthesis of the linearly fused [6.5.5] tricyclic system, starting from 6, encouraged us to apply a similar sequence of transformations for 1-ethynylcyclopentene 28 with the hope of arriving at the [ 5 . 5 . 5 ] tricyclic framework common to many

J. Am. Chem. Soc., Vol. 114, No. 14, 1992 5559

Stepwise AdE and intramolecular Pauson-Khand Reactions Scheme VI1

Scheme VI11 M

I . CO,(CO),

Me0

m -2 . [2 + 2 +I], 5OPC,8h, LPC 52%

1, CO,(CO),

a-

+ 2 +I], 50QC,6h, LPC 2 . j2

2Lc

&zu

68%

Wo+

CH

H, L

6 0 T , 8h, LPC 70PC,10h, DSAC

a :b = 1

1. co,(co)8

2.a

CH

m

J

34 ' U X~BA

7% 5%

47% 53%

HO Me

3lLk

' M e

m

MeMgl

'

93% 1.2

1. CO,(CO),

no cvcltzation

2. SiO,.

6Op-10OQC,6-14h

(DSAC), or hexane, 6WC, 6h (LW

*

Scheme IX

2 . [a + 2 +I]. 50QC,8h, LPC

&

2u

78%

natural triquinanesU6One might have anticipated that in this case the stereochemical problems would be much more critical in comparison with the synthesis of the [6.5.5] system described above. In fact, it is well known that, due to the steric strain, trans fusion of fivemembered rings is extremely unfavorable6"and hence the application of the IMPK reaction for the construction of this system requires the use of precursors having 1,2-cis-oriented ethynyl and propenyl groups. Albeit the ease of acylmethoxylation of 28 is well documented,& at the beginning of this study no reliable data were available on the steric course of this reaction. By analogy with the data on the stereochemistry of the AdE reactions in the cyclohexene series (see Schemes IV and V), we did not expect any special problems in securing the preparation of the necessary stereoisomers by the standard procedure of acylmethoxylation of 28. In fact the reaction of 28 with 7 proceeded quite cleanly and gave (after quenching of the reaction mixture with MeOH at -20 "C) the corresponding adduct DCHCC 29 in a fair yieldi0 (Scheme VIII). Oxidative decomplexation converted 29 into a crystalline crotonoyl methoxy adduct 30. However, much to our dismay, an examination of its structure by X-ray single-crystal analysis revealed that the latter had the structure of (lR*,2S*)-l-methoxy-lethynyl-2- [ (E)-l'-oxobut-2'-enyl]cyclopentane! Thus the acylation of 28 also proceeded stereospecifically but as an exclusive cis addition across the double bond, in striking contrast to the aforementioned data relating to the similar reaction performed with 6. Nevertheless, some attempts were made to check the possibility of carrying out the IMPK reaction in the cyclopentane series with a 'wrong" configuration of the reacting side chains. To this aim, 30 was converted into the secondary allyl alcohols 31s,b (by 1,Zhydride reduction) or into the tertiary allyl alcohols 32a,b (by 1,Zaddition of MeMgI at -70 "C). Not unexpectedly, DCHCC derived from both 31 and 32 failed to undergo cycloaddition under all conditions tested (LFCor DSAC), and the starting materials were either intact or turned into an untractable tar. Cyclization was also not observed with ketone 30 (Scheme VIII). These results forced us to look more thoroughly at the problem of control over the stereochemistry of the acylmethoxylation of 28. Earlier data on the acylation of 6, revealed that the stereochemistry of the final adduct could vary depending on the conditions used for the quenching of the carbocationic intermediate (CCI) with a nucleophile.2a~cThus the treatment of the CCI formed upon the interaction of 6 with various acylium cations with

RCO'Y'

+

I

Step 1

€ail Step 2

t &m trans

adduct

c i s adduct

MeOH at -70 O C followed by an immediate neutralization with a base at low temperature led to the formation of a mixture of cis and trans adducts. At the same time almost exclusive formation of the trans adduct (such as 8,16a, or 18a, see above) was observed when the reaction mixture formed upon the quenching of the CCI with MeOH was allowed to warm up to -20 O C and was kept for 1-2 h at this temperature prior to neutralization with a base (the conditions used in the reactions are shown in Schemes IV and V). Rationalization of these data was givenZCin terms of the nonstereoselectivity of the quenching of CCI-1 under kinetic control and the possibility of further equilibration (in the absence of the base) of the initially formed mixture of stereoisomeric protonated methoxy adducts CCI-2 (via eliminationaddition) into the more stable trans adduct (Scheme IX). To check the possibility of exerting similar control in the addition across the double bond of the five-membered, ring we have studied the course of the acylmethoxylation of 28 with 17. The reaction mixture formed upon addition of the acyl cation was quenched with MeOH at -70 O C and then either (i) neutralized immediately with pyridine at this temperature or, alternatively, (ii) warmed up to 20 OC, kept for 30 min at ambient temperature, cooled to -70 "C, and neutralized again with pyridine. In apparent corroboration of the data discussed above for the reactions with

Gybin et al.

5560 J. Am. Chem. SOC.,Vol. 114, No. 14, 1992 Scheme X

Scheme XI

L

CCI-2

L

d

H O

0

m adduct

case ( I ) : MeOH. -70%2, C,H,N case (ii)MeOH, -70% -20'C,

CIS

:

:

= 1 : 1 1,

2

40% a:b=9.1

5 a ~ ~ c :d=7'3

63% 60%

u c

1 CO,(CO),

u

35a.b adduct

30min. C,H,N:

85%

35c.d-

90% a : b = 1: 1.2

$pel

, "*I

trans

3LLb

M

- q;;-.l m

J

o

d=15

a,R=H

95%

cm,

1

no cycloadducts

SIO,, 60-100eC, 1-5h

6, the kinetically formed product (case i) was comprised of a nearly 1:l mixture of two isomers, 33a and 33b. As was expected under the conditions of thermodynamic control (case ii), a practically pure single isomer 33b was formed. Unfortunately, analysis of the IH NMR spectrum of the corresponding decomplexed sample did not allow us to determine the stereochemistry of 33b. Hence, an attempt was made to use 33b as the starting compound for preparation of the tricyclic product. The sequence of the oxidative decomplexation and dehydrochlorination gave 34b, which further underwent smooth 1,2-hydride reduction with the formation of allyl alcohols 35c,d (Scheme X). All attempts to use 35c,d as substrates for IMKP cyclization, however, proved to be futile. These results unequivocally indicated a cis orientation of addends in 33b in spite of the fact that the latter was prepared under conditions previously and quite successfully used for preparation of the desirable trans adduct in the cyclohexane series. It became obvious then that pursuing our goal could be achieved only with the use of isomer 33a as a starting material. To check this option, the above mentioned mixture 33a,b was subjected to oxidative decomplexation followed by dehydrochlorination (Scheme XI). The mixture of stereoisomers, 34a,b thus formed was reduced to the mixture of alcohols 35a-d. After separation by chromatography, pure isomer 35a was isolated in 36% yield. To our delight, this product turned out to be a very suitable precursor for the IMPK reaction. In fact treatment of 35a with C O ~ ( C Ofollowed )~ with heating of the resulting Co complex under DSAC gave the required product, 2-methoxy-7hydroxytricyclo[6.3.0,02~6]undec-l 1-en-10-one 36a,b, in 74% yield. It has also been found that the entire sequence 33 36 can be carried out without a chromatographic separation of the stereoisomeric intermediates. In this case, products 36a,b were obtained in a yield of ca. 30%, which roughly corresponded to the percentage of the reactive isomer in the initial mixture. As is shown in Scheme XI, the resulting cycloadduct represents a mixture of diastereoisomers 36a and 36b. Acetylation of this mixture followed by TLC separation afforded individual tricyclics 37a and 37b. The structure of 37a as (2R*,6S*,7R*,8R*)-7acetoxy-2-methoxytricyclo[6.3.0.02.6] undec- 1 1-en- 10-one represented in Scheme XI was elucidated by X-ray analysis. The stereochemistry of isomer 37b was deduced from comparison of IH N M R spectral patterns and observation of NOES for both isomers. IMPK Cyclizations with the Participation of a Conjugated Double Bond in the Synthesis of Polycyclic Compounds. While we were trying to optimize the procedure for the preparation of

-

3 8 % c

R=Ac

R=H 36%

R=Ac

Scheme XI1

[-HCI]L

0

0

u

34

[-MeOH]

MO+ (-$yo+ eo Me

0

0

3, 27%

3-4

SiO,

41,23%

90°C, 10h

* 40 (2%) +

0

42,4 %

u (49%)

25, attempts were made to carry out the dehydrochlorination of 23 over basic A1203without prior decomplexation of 23 into 24 (Scheme VI). TLC monitoring revealed that HCl elimination with 23 proceeded easily even at rmm temperature, but in addition to the target product 38 (DCHCC of 25; Scheme XII), metal-free and more polar compounds were formed in varying amounts. Under slightly more forceful conditions (60 "C), the conversion of 38 into these products was complete within 10 h. Much to our surprise (and delight) we discovered that the resulting mixture was comprised mainly of the tricyclic products 40-42 formed in a satisfactory total yield (Scheme XII). Thus, in spite of the presence of the carbonyl functionality in conjugation with the double bond, adduct 38 turned out to be amenable to the IMPK reaction under the conditions mentioned. The structures of 40-42 were deduced from their spectra (IR, UV, HRMS, and NMR). Thus the UV spectra of 41 and 42 revealed the presence of adsorption bands with , , X 235 and 237 nm, respectively, indicative of the presence of an a,b-disubstituted 117 cyclopentenone moiety. For 40, two band appeared with A, and 292 nm, typical for the presence of an extended dienedione system. The presence of the latter is also indicated by the appearance of adsorption bands at 1596 and 1608 (conjugated double bonds) and 1706 with a shoulder at 1698 cm-' (carbonyl groups) in the IR spectrum for 40. IR spectra of 41 and 42 indicated the presence of one double bond (1658 cm-') and two carbonyl groups (1706 and 1748 cm-I). The IH NMR spectrum of 40 contained a singlet at 6 5.73 ( H at C-12) and an AB multiplet at 6 2.27 and 2.44. IH N M R spectra of 42 revealed an AA'BB' multiplet of four a-carbonyl protons with small long-range coupling constants

Stepwise Ad, and Intramolecular Pauson-Khand Reactions Scheme XI11

J. Am. Chem. Soc., Vol. 114, No. 14, 1992 5561 Scheme XIV

w

90%

2 :1

4e

53%

m [2 + 2 +1]

G

between protons at C-10 and C-12; for 41, protons at C-12 were additionally coupled with a proton at C-1. 13CN M R spectra of 40-42 indicated the presence of 13 carbon atoms having the expected pattern of chemical shifts (see the Experimental Section). The stereochemistry of 42 is substantiated by the observation of NOES. A similar configuration for 41 is ascertained by the noticeable upfield shift of the Me signal in its 13CN M R spectrum (y-gauche effect of hydroxyl group) as compared with the respective signal for 42. The results shown in Scheme XI1 implied that under DSAC a series of consecutive reactions with 23 occurred, namely, rapid dehydrochlorination leading to 38, IMPK cyclization of the latter accompanied by elimination of methanol giving 40,and Michael addition of water (from A1203) across the less hindered site of 40 leading eventually to 41. The same mixture 40-42 was also obtained by the cyclization of preformed adduct 38 over A1203. One can reasonably assume, then, that the IMPK reaction initially produces the tricyclic methoxy enone 39. In fact, TLC data indicated the transient appearance of another polar product at the initial period of the cyclization. We were unable, however, to isolate 39 in a pure state due to the ease of its transformation into a mixture of 40 and 41 in the course of the attempted isolation by PTLC (on Fluorisil). The presence of 39 in this mixture was ascertained by M S and IH N M R data (appearance of the respective molecular ion M+ 234 and signals of methoxy groups at 6 3.13 and 3.20). Formation of the product 42 indicated the Occurrence of hydrogenation in the course of the IMPK reaction, a process not without p r e c e d e n ~ e . ~ ~This . ' ~ side reaction can be suppressed if the conversion is carried out in an O2atmosphere, but the total yield of the tricyclic product is decreased due to the partial decomplexation of the starting material. The cyclization of 38 over SiOz occurs more sluggishly and results in the formation of 42 as the major product (Scheme XII). It is significant that, prior to this study,Is not a single example of the IMPK reaction involving the participation of a conjugated double bond could be found among the numerous publications dealing with this reaction.jb To evaluate the scope of the applicability of this discovery, we studied the possibility of performing this transformation for some related acylmethoxy adducts. Interaction of 6 with 2 under standard conditions of acylmethoxyacylation gave the expected adducts 43a,b in 85% yield (a mixture of diastereomers in a ratio of 2:l) (Scheme XIII). This mixture, when applied to the surface of Fluorisil, underwent a smooth IMPK reaction and gave a tetracyclic product 44 in good yield. The structure of the latter was unequivocally proven by singlecrystal X-ray analysis. It was also shown that the individual isomers 43a and 4% were converted into the same product 44 with a comparable rate. In a similar way, reaction of 28 with 2 gave adducts 46a,b in nearly quantitative yield (a:b = 1:3, Scheme XIV). Trial experiments reveal that only isomer 46a, obviously with a cis orientation of the ethynyl and acyl substituents is able to undergo an IMPK reaction (both under DSAC and LPC), while 46b can (14) See also, for example: Montana, A. M.; Moyana, A.; Pericas, M. A.; Serratosa, F. Tetrahedron 1985, 41, 5995. (IS) Veretenov, A. L.; Smit, W. A.; Vorontsova, L. G.; Kurella, M. G.; Caple, R.; Gybin, A. S. Tetrahedron Leu. 1991, 32, 2109.

97%. a : b = 1 : 3

0-

g1. BF,, CH2C12, -7O'C

499

73%

*+m, 85%

2. MeOH

1 .3

ea be recovered intact (cf. with the data in Schemes X and XI). In a preparative run with a mixture of 46a,b, the respective tetracyclic product 47 was obtained as a single isomer in ca. 70% yield (calculated for the content of reactive isomer 46a in the initial mixture) (Scheme XIV). In this case, no methanol elimination was observed. The recovered 46b could be equilibrated into the same 1:3 mixture of 46a,b upon treatment with BF, in CH2CI2 at -75 "C (MeOH quench, yield ca. 85%). The structure of 47 was established by single-crystal X-ray analysis. The attempts to carry out the IMPK reaction with several other AdE adducts like 8 or 15 failed. At best, only trace amounts of the respective tricyclic products were identified in the reaction mixtures. It seems reasonable to speculate that the increased propensity of 38, 43, and 46a to undergo the IMPK reaction is related to the presence of the additional substituents at the a-atom of the double bond, which may serve as a factor restricting the conformational mobility of the side chain in such way that the double bond becomes more proximate to the reacting Co-complexed moiety.I6 These limitations notwithstanding, the reaction sequences shown in Schemes XII-XIV offer some promising options for the preparation of the polycyclic compounds useful for the synthesis of various polyquinanes.6a*bThus, the tetracyclic compound 44, which was prepared in two operationally simple steps from readily available precursors, contains the basic BCDE rings framework present in the structure of retigeranic acid 45.17 Pathways leading to the synthesis of the latter compound, via an approach similar to that shown in Scheme XIII, are being actively pursued in our group. It is also to be emphasized that the natural tetraquinane crinipellin-B (48)18 contains the same tetracyclo[6.6.0.0'*11.03-7]tetradecane skeleton as the adduct 47. Prior to our studies, this framework had never been synthesized, and only recently some models containing this system were prepared by a multistep reaction sequence.18 Summary. The results presented clearly indicate the viability of the approach suggested earlier4av5as a general and practical route for the synthesis of polycyclic compounds. The short sequence of transformations leading from available starting materials to rather complicated polycyclic compounds (16) One of the reviewers suggested that "perhaps the reason why the normal Pauson-Khand products are formed in Smit's case are (1) opposite polarization of the alkene compared to other intermolecular examples that yield dienes, and (2) no &hydrogen is present to be removed after the cycloaddition". While this explanation also seems to be feasible, we believe that the final assessment of the relative importance of various factors affecting the ease of this reaction cannot be made on the basis of the available experimental data related to a rather limited set of the substrate structures. (17) Corey, E. J.; Desai, M. C.; Engler, T. A. J . Am. Chem. SOC.1985, 107, 4339. (18) Mehta, G.; Srinivas Rao, K.; Sreenivasa Reddy, M. J . Chem. SOC.,

Perkin Trans. 1991, 693 and references cited therein.

5562 J. Am. Chem. SOC.,Vol. 114, No. 14, 1992 seems to be unprecedented. In general, it involves only three reactions: (i) AdE acylmethoxylation of the double bond of DCHCC of conjugated enynes leading to the formation of DCHCC of 1,6-enynes; (ii) transformation of the carbonyl group of these adducts; and (iii) IMPK reaction. For several model systems this sequence can be reduced to only two reactions, i and iii. The stepwise AdE reaction used at the beginning of this sequence represents a fairly general protocol for the assemblage of the basic 1,6-enyne moiety which can thus be incorporated within various structural surroundings. The flexibility of this reaction is well established by the previously shown opportunities to vary the nature of all three building blocks utilized in this process, namely, 1,3-enynes, acylium electrophiles, and to a lesser extent, nucleop h i l e ~ . ' , Therefore, ~,~ the synthesis of structurally different precursors bearing this fragment can be reached along a unified and a convergent route. It is noteworthy that in the previously described preparations of bi- and tricyclic compounds, which included utilization of the IMPK reaction a t the ring-forming step, the synthesis of the utilized 1,6-enyne precursors usually required rather long and tedious procedure^.'^ The second reaction involving 1,2-reduction of a carbonyl group in conjugation with a double bond is, essentially, an auxiliary step necessary to transform initial AdE products into substrates amenable to IMPK cycloaddition. One can easily envisage, however, the constructive utilization of this operation, e.&, via the use of functionally substituted Grignard reagents. Also fortunate is that, at least in some cases, this step can be avoided completely. The final step of the described approach is based on the well-known IMPK reaction. The use of this reaction for the syntheses of angularly fused tricyclics has already been described.9a% The data given in this paper provide additional evidence concerning the scope and stereochemistry of the process. An application of the IMPK reaction for the synthesis of linearly fused tricyclic compounds from monocyclic precursors had never been reported. Our data demonstrated the special efficiency of this approach for the preparation of the tricyclic [6.5.5] fused system with both trans and cis junctions of the [6.5] system, depending on the stereochemistry of the precursors. The IMPK cyclization in this series proceeds in a highly stereoselective manner. Less promising results were obtained in the [5.5.5] series. Here the cyclization of precursors with cis-oriented reacting moieties can be performed very efficiently (albeit with a low stereoselectivity). However the problem of securing the required stereochemistry in the course of the preparation of these precursors turned out to be nontrivial, and additional studies are necessary to solve this problem. The opportunity to create tetracyclic systems by a simple tandem sequence of AdE plus IMPK reactions described above deserves special mention as a novel and a very prospective convergent route to various natural compounds, and the ramifications of this finding are currently under intensive study. Some of the observed limitations of the suggested approach also seem to be worth mentioning. The most serious refers to the low stereoselectivity observed in some of the IMPK reactions. However, it seems justified to hope that modifications of the structures of the reactants and/or of the reaction conditions may provide some opportunities to avoid or at least to mollify these complications.20 (19) Compare with the procedures described in ref 9a,b. See also: (a) MacWhorter, S. E.; Schore, N. E. J. Org. Chem. 1991,56,338. (b) Magnus, P.; Principe, L. M.; Slater, M. J. J . Org. Chem. 1987, 52, 1485. (c) Magnus, P.; Exon, C.; Albaugh-Robertson, P. Tefrahedron 1985.24, 5861. (d) Hua, D. H. J . Am. Chem. SOC.1986, 108, 338. (e) Castro, J.; Sorensen, H.; Riera, A.; Morin, A,; Moyano, A.; Pericas, M. A,; Green, A. E. J. Am. Chem. SOC. 1990, 112, 9388 and references cited in these publications. (20) While there is no general solution to the problem of control over the stereoselectivity of the IMKP reaction, several possible options are suggested, as mentioned in ref 3b. For recent data, see: (a) Poch, M.; Valenti, E.; Moyano, A,; Pericas, M. A,; Castro, J.; DeNicola, A,; Green, A. E. Terrahedron Left. 1990, 31, 7505. (b) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tefrahedron Lett. 1990, 37, 5289.

Gybin et al. It seems also relevant to comment that the syntheses of the triand tetracyclic systems described in this paper are based on the sequential and controlled functionalization of the starting 1,3-enyne system, which is eventually used as the synthetic equivalent of a tetradentate synthon. In these sequences the Cc-carbonyl moiety is utilized as a multipurpose group which ensures protection of the triple bond at the initial step of electrophilic attack a t the double bond and stabilization of the incipient carbocationic intermediateZ1and finally serves as a reacting function in the cyclization step at the end of the sequence. Some final remarks should be made about the observed effects of adsorption on the efficiency of [2 2 11 cycloadditions. In line with our previous observation^,^ DSAC turned out to be the procedure of choice for the reactions with 4a,b, 10, 11, 35a, 38, and 44,while in other examples LPC worked equally well. Similar beneficial effects of the utilization of DSAC on the course of the IMPK reaction22as well as on some other transition metal mediated cyclization^^^ have recently been reported. While some suggestions have been advanced to account for the observed p h e n ~ m e n a , ' ~the ? ~ ,latter ~ ~ is still little understood and a t best can serve to attest to the necessity and promise of more detailed studies in this area.24

+ +

Experimental Section General. ' H N M R spectra were recorded on a Bruker WM-250 spectrometer and the "C spectra on a Brucker MA-300 spectrometer for CDCI3 solutions with TMS as an internal standard. Mass spectra were obtained on a Varian MAT CH-6 (70 eV). Determinations of exact mass were carried out with a J M S D-300. Microanalyses were performed on a Perkin-Elmer 240 instrument by the Analytical Department of the Zelinsky Institute of Organic Chemistry. The analytical TLC plates used were Silufol UV-active silica gel on aluminum foil (Czechoslovakia). Unless specified, preparative isolation and separation of isomers were achieved on plates 22 X 24 cm with unfixed SiOz (LSL 40/100 pm or Silpearl, both from Czechoslovakia, 2 mm layer, PTLC). DCHCC of acetylenic compounds were prepared by the treatment of appropriate precursors with C O ~ ( C Oas) ~described elsewhere (e.g., data in ref 4d). DCHCC 6 and 28 were prepared by the dehydration of DCHCC of 1-ethynyl- 1-hydroxycyclohexene and -cyclopentene, respectively, in accordance with the following general procedure. To a stirred solution of the starting carbinol (IO mmol) in CH2CI2was added freshly distilled BF,.Et20 (0.45 g, 4 mmol) at 20 "C. The mixture was stirred for an additional 5 min and then quenched by Et,N (0.45 g, 4.5 mmol) and filtered through SiOz (3 mm). After removal of the solvent, the residue was dissolved in pentane or ether and separated from the traces of black precipitate by additional filtration through SO2. Removal of the solvent under reduced pressure gave practically pure complex 6 or 28 in nearly quantitatively yield (90-95%) from the corresponding conjugated enynes. Oxidative decomplexation of DCHCC was carried out with Ce(NH4)2(NO,), by the modified procedure" as follows. Ce(NH4)2(N03)6(2.74 g, 5 mmol) was dissolved in acetone (6 mL) and cooled down to -30 to -35 "C. A solution of DCHCC (1 mmol) in acetone (1 mL) was added, and after 5 min the mixture was quenched with ether-water (50 mL, 91). The ethereal layer was washed with water and dried over Na2S04. Removal of the solvent gave the corresponding adducts in nearly quantitative yields. Unsaturated acyl fluorides used for the generation of acylium cations 2, 7, and 14 were prepared by the dictillation of the respective chlorides over anhydrous ZnF2;Pc,d3-chloropropionyl fluoride and 2-methyl-3-chloropropionylfluoride used as the precursors for the generation of 16 and 22, respectively, were obtained by reaction of the respective acyl chlorides with liquid H F in accordance with a general procedure described earlier.25 Acyl fluorides were purified by distillation (yields 60-80%) and stored over anhydrous N a F in the freezer. Electrophilic agents, acylium tetrafluoroborates, were generated in situ by interaction of respective acyl fluorides with an excess of gaseous BF, (21) For the properties of Co-stabilized propargyl cationic species, see a review: Nicholas, K. M. Arc. Chem. Res. 1987, 20, 207. (22) (a) Jeong, N.; Yoo, S.; Lee, S. J.; Lee, S. H.; Chung, Y. K. Tetrahedron Left.1991,32, 2137. (b) Roush, W. R.; Park, J. C. Tetrahedron Left. 1991, 32,6285. (c) Smit, W. A.; Kireev, S. L.; Nefedov, 0. M.; Tarasov, V. A. Tefrahedron Left. 1991, 32, 4021. (d) Brown, S. W.; Pauson, P. L. J . Chem. Soc.. Perkin Trans. I 1990, 1205. (23) Katz, T. J.; Yang, G. X . Tetrahedron Left. 1991, 32, 5895. (24) For a general survey of surface-promoted reactions, see: Preparative Chemistry Using Supported Reagents; Laszlo, P., Ed.; Academic Press: New York, 1987. (25) Olah, G. A.; Comissarov, M. B. J . Am. Chem. SOC.1966,88,4442.

J . Am. Chem. SOC.,Vol. 114, No. 14, 1992 5563

Stepwise AdE and Intramolecular Pauson-Khand Reactions introduced by a syringe. All reactions were conducted under an argon atmosphere. C O ~ ( C OComplex )~ of 3-Methoxy-5-(cyclopent-l’-en1’-yl)pent-I-yn5-one (3). To a stirred solution of DCHCC of vinylacetylene 1 (0.76 g, 2.25 mmol) in CH2CI2(40 mL) at -78 OC was added 1-cyclopentenoyl fluoride (0.34 g, 3.0 mmol) and then gaseous BF3 was introduced (200 mL, ca. 8 mmol). The mixture was stirred until TLC monitoring indi-

cated complete disappearance of the starting material (10 min), quenched with absolute MeOH (5 mL), warmed up to -40 OC, and poured into a stirred mixture of aqueous NaHCO,-ether. After separation and additional extraction with ether, the organic layer was thoroughly washed with aqueous N a H C 0 3 and water and dried over Na2S04. Solvent evaporation gave practically pure 3 (TLC, IH NMR) as a dark red oil (1.03 g, 9896, R, = 0.35, benzene), which was used without additional purification. To ascertain the structure, a portion of 3 was decomplexed (Ce4+,see above; yield 95%) into 3-methoxy-5-(cyclopent-l’-en-l’-yl)pent-I-yn-5-one (3a): IH NMR 6.78 (1 H, m), 4.49 (1 H, ddd, J = 2.2, 5.0, 8.0 Hz), 3.4 (3 H, s), 3.2 (1 H, dd, J = 8.0, 16.0 Hz), 2.9 (1 H, dd, J = 5.0, 16.0 Hz), 2.46 (1 H, d, J = 2.2 Hz), 2.55 (4 H, m), 1.9 (2 H,

m) . CO~(CO)~ Complex of 3-Methoxy-5-(cyclopent-1’-en-1’- yl)pent- I-yn5-01 (4). To a stirred solution of 3 (0.83 g, 1.8 mmol)in MeOH (18 mL) were added sequentially CeCI3.7H2O (0.69 g, 1.85 mmol)and, after the mixture was cooled down to -50 OC, NaBH4 (0.076 g, 2 mmol). After

5 min, ether (50 mL) was added, the reaction mixture was filtered through Si02, and the solvent was removed. The residue was dissolved in ether (20 mL) and again filtered through S O 2 . Removal of the solvent and separation of the residue (PTLC, eluent CHCI,-Et20, 20:l) gave individual 4a (0.47 g, 56%) and 4b (0.31 g, 37%) as red-purple liquids (R/=0.50 and 0.41, respectively, both C&-Et@, 6:1), MS m / e 298 (M+ - 6CO) (for both isomers). For identification, samples of 4a and 4b were converted (by oxidative decomplexation) into respective metalfree 4aa and 4ba (yields > 90%). For 4aa: IH NMR 5.63 (1 H, m), 4.53 (1 H, m),4.18 (1 H, ddd, J = 2.2, 5.0, 7.0 Hz), 3.42 (3 H, s), 2.48 (1 H, d, J = 2.2 Hz), 2.3 (4 H, m), 1.9 (4 H, m). Anal. Calcd for CllHI6O2:C, 73.30; H, 8.95. Found: C, 73.45; H, 8.79. For 4ba: ‘H NMR 5.63 (1 H, m),4.48 (1 H, dd, J = 4.3, 9.0 Hz), 4.16 (1 H, ddd, J = 2.2, 6.0, 8.0 Hz), 3.43 (3 H, s), 2.50 (1 H, d, J = 2.2 Hz), 2.3 (4 H, m), 2.03 (1 H, ddd, J = 14.0, 6.0, 4.3 Hz), 1.95 (1 H, dd, J = 14.0, 9.0, 8.0 Hz), 1.88 (4 H, m). Anal. Calcd for CllHI6O2:C, 73.30; H, 8.95. Found: C, 73.57; H, 8.82. 4-Methoxy-2-hydroxytricyclo[6.3.O.O1~s]undec-5-en-7-one (5). Chromatography grade silica gel (Silpearl, 5 g, 100-120 Mm, Chemapol, Czechoslovakia,26 water content ca. 15%) was added to the solution of 4a (0.57 g, 1.22 mmol) in hexane-ether (20 mL, 1:l). After removal of the solvent on a rotovap, the orange powder was kept under vacuum for 10 min, and the reaction vessel was flushed with Ar. This procedure was repeated three times to remove traces of oxygen. The vessel was sealed and heated at 100 OC for 1 h (conditions required for the complete consumption of the starting material, TLC control). The resulting gray powder was washed with ether (2 X 25 mL) and methanol (3 X 25 mL). After solvent removal, the brown residue (0.338 g) was chromatographed to give a mixture 5a.b (0.103 g, yield 41%) as a colorless oil (5a:Sb = 3:5, IH NMR), MS m / e 208 (M’) (for both). This mixture was further separated by PTLC (Silpearl, elution with ether, three runs) into individual Sa and Sb (Rf= 0.49 and 0.45, ether, respectively). Sa: colorless plates, mp 128-129 ‘c (pentane). Anal. Calcd for Cl2HI6o3:c, 69.21; H, 7.75. Found: C, 69.07; H, 7.82. Sb: colorless oil. Anal. Calcd for CI2Hl6O3:C, 69.21; H, 7.75. Found: C, 68.92; H, 7.63. IH and I3C NMR data for Sa,b are given in Tables I and 11. The structure of 5a as

yield 92%, colorless oil; IH NMR 6.86 ( I H, dq, J = 6.9, 15.5 Hz), 6.34 (1 H , d q , J = 1.8, 15.5 Hz), 3.34(3 H,s), 2.83 (1 H,dd, J = 3.8, 11.0 Hz), 2.64 (1 H, s), 1.87 (3 H, dd, J = 1.8, 6.9 Hz), 1.2-2.3 (m,8 H). The identity of 9 was ascertained by comparison (TLC, IH NMR) with an authentic sample as described earlier.2a

(1R *,2R *,1’R)-l-Methoxy-l-ethynyI-2-[(E)-l’-hydroxybut-2’-en-l’yllcyclohexane (10) was prepared from 9 as outlined above for 4a,b, but the reaction was carried out at 0-5 OC. Reduction of 9 (0.54 g, 2.6 mmol) gave 10 (0.49 g, yield 91%). Only one diastereomer was formed (‘H and ”C NMR data), and it was used without additional purification: IH NMR 5.8-5.5 (2 H, m),4.65 (1 H, m),3.41 (3 H, s), 2.71 (1 H, s), 2.23 (1 H, ddt, J = 1.6, 3.3, 11.9 Hz), 1.7 (3 H, dt, J = 1.8, 6 Hz), 1.1-1.8 (9 H, m);13CNMR 132.8 (C-2’), 125.1 (C-3’), 83.4 (C-7), 78.1 (C-l’), 76.3 (C-l), 71.8 (C-8), 52.5 (C-2), 50.5 (MeO), 37.0, 25.5, 23.5, 23.1 (C-3-C-6), 17.5 (C-4’); MS m / z 208 (M’).

(1R *,2R *,l’R)-l-Methoxy-l-ethynyI-2-[(E)-1’-acetoxybut-2’-en-1’yl]cyclohexane (11). A mixture of 10 (0.49 g, 2.36 mmol),Ac20 (0.72 g, 7.05 mmol), Et,N (0.71 g, 7.05 mmol), and 4-DMAP (0.02 g) was stirred at 20 ‘C for 40 min. E t 2 0 (70 mL) was added, and the mixture was washed with 3% aqueous HCI, water, NaHCO,, (3 X 25 mL), and water and dried over Na2S04. Removal of the solvent gave individual 11 (0.548 g, yield 93%) as colorless crystals: mp 86-87 OC (hexane); IH NMR5.84(1H,m),5.64(1H,ddq,J= 15.4,6.3,1.1Hz),5.43(1H, ddq, J = 15.4, 6.2, 2.0 Hz), 3.37 (3 H, s), 2.48 (1 H, s), 2.23 (1 H, ddt, J = 12.1, 3.2, 1.5 Hz), 2.02 (3 H, s), 1.68 (3 H, dt, J = 6.3, 2.0 Hz), 1.1-1.8 (8 H, m);MS m / z 250 (M+); exact mass found M+ 250.1576, CISH2,O3requires 250.1569. The structure was proven by X-ray analysis. 10-Methyl-8-hydroxy-2-methoxytricyclo[7,1 (12)-en-11one (12a,b). CO,(CO)~(0.75 g, 2.19 mmol) was added to a stirred solution of 10 (0.416 g, 2.0 mmol) in E t 2 0 (15 mL) at 20 ‘C. After 45 min the evolution of CO ceased. The dark red solution was mixed with S i 0 2 (Silpearl, 120-140 wm,water content ca. lo%, 12.5 g), the solvent was removed under reduced pressure, and the red powder was heated at 50 OC for 4 h. The silica gel was washed with E t 2 0 (6 X 25 mL), and the residue, after solvent removal, was chromatographed on Si02to give a small amount of the starting material 10 (0.087 g, yield 9%) and a mixture of 12a,b (0.41 g, semicrystalline solid, yield 87%, Rf = 0.39 (ether), a:b = 3.8:1, IH NMR). Recrystallization from benzene-hexane (1:l) gave 0.238 g of the 2R*,7S*,8R1,9S*,10S* isomer 12a, colorless crystals, mp 97-98 “C (hexane-ether), and 0.16 g of the mixture 12a,b, MS m / e 236 (M+), 204 (M+ - MeOH) (for both). For 12a, exact mass found M+ 236.1419, Cl,H2003requires 236.1412; NMR spectra, see Tables 111 and IV. The cyclization of 10 under LPC (hexane, 60 OC, 2 h, complete conversion of 10) gave the same mixture 12a,b in 39% yield. 10-Metbyl-8-acetoxy-2-methoxytricyclo[7.3.0.0z ’)dodec- 1( 12)-en-11one (13) was obtained as a mixture of stereoisomers 13a,b by the cyclization of 11 (0.21 g) on SiOz (60 OC, 0.5 h) in 73% yield (R,= 0.53, ether, a:b = 3.3:1, ‘ H NMR), which were separated by PTLC into individual 1311 (R,= 0.5, ether) and 13b (R,= 0.55, ether). For NMR spectra, see Tables 111 and IV. 13a: MS m / e 278 (M’); exact mass found M+ 278.1511, C16H2204 requires 278.1518. 13b: MS m / e 278 (M’), 218 (M+ - CH,COOH). The identity of the products was additionally ascertained by IH NMR comparison with authentic samples prepared by acetylation of 12s and

12b.

C02(CO)6 complex of l-methoxy-I-ethynyl-2-(l’-oxoprop-2’-enyl)cyclohexane (15) was prepared as described above for 3 from 6 (0.39 g, 1 mmol),acryloyl fluoride (0.22 g, 3 mmol),and BF3 (125 mL, 5 mmol). After TLC separation, 15 (0.11 g, yield 24%, R, = 0.61, hexane-ether, ( 1R*,2S*,4S*,8R*)-4-methoxy-2-hydroxytricyclo[6.3.O.O~~s]undec-5-en-1O:l) was obtained as a dark red liquid. IH NMR spectra of the de7-one was established by X-ray analysis. complexed product 16 indicated the presence of two stereoisomers in a A mixture of stereoisomers Sc,d was obtained similarly upon the cyratio of ca. 8:l. For the major 1R1,2R* of isomer 16a: IH NMR 6.58 clization of 4b (0.65 g, 1.39 mmol) on SiO, (5.5 g). Separation of this (1 H , dd, J = 17.1, 9.0 Hz), 6.22 (1 H, dd, J = 17.1, 2.8 Hz), 5.66 (1 mixture by PTLC (vide infra) produced individual isomers as colorless H, dd, J = 9.0, 2.8 Hz), 3.35 (3 H, s), 2.89 (1 H, dd, J = 10.9, 3.3 Hz), liquids, Sc (0.046 g, yield 16%. R, = 0.68, ether), and 5d (0.042 g, yield 2.63 (1 H, s), 2.29 (1 H , m), 1.2-1.8 (7 H, m). 1475, R = 0.56, ether). Sc: Anal. Calcd for Cl2HI6o3:C, 69.21; H, Co2(CO), complex of l-methoxy-l-ethynyl-2-(3’-chloro-l’-oxo7.75. iound: C, 68.89; H, 7.58. Sd: Anal. Calcd for C l 2 H I 6 o 3 c: , propy1)cyclohexane (18a,b) was prepared from 6 (1.24 g, 3.1 mmol), 69.21; H, 7.75. Found: C, 68.80; H, 7.50. 3-chloropropanoyl fluoride (0.86 g, 7.9 mmol),and BF, (355 mL, 14.2 CO~(CO)~ complex of (1R *,2R *)-l-methoxy-l-etbynyl-2-[(E)-l’- mmol) as was described for 3. Removal of traces of 6 by filtration oxobut-2’-enyl]cyclohexane (8)was prepared as described above for 3 through a short column with SiO, gave 18a,b as a dark red liquid (1.54 from DCHCC of 1-ethynylcyclohexene 6 (2.16 g, 5.5 mmol),crotonoyl g, yield 95%, R,= 0.55, hexane-ether, lO:l), which was further decomfluoride (0.97 g, 11 mmol),and BF3 (413 mL, 16.5 mmol). PTLC gave plexed into 19a,b (yield 95%. a:b = 9:1, IH NMR). Major isomer 1911: 8 as a dark red oil, 1.41 g (yield 52%).1° The product was used without ‘ H NMR 3.7 (2 H, m),3.35 (3 H, s), 2.63 (1 H, s), 2.59 (1 H, dd, J = additional purification. 8.2, 4.0 Hz), 2.26 (1 H, m), 1.2-1.8 (7 H, m); MS (mixture 19a,b) m / z (1R *,2R*)- I-Methoxy-l-ethynyl-2-[(~)-l’-oxobut-2’-enyl]cyclo230, 228 (M+), 215, 213 ( M + - Me), 199, 197 ( M + - MeO), 193 (M+ hexane (9)was prepared by oxidative decomplexation of 8 (vide infra): - CI). The mixture was used without additional purification. I-Metboxy-1-ethynyl-2-( l’-oxoprop2’-enyl)cyclobexane (16a,b). A solution of 19a,b (0.64 g, 2.8 mmol) in pentane (10 mL) was mixed with (26) The use of silica gels of different brands (e.g., Aldrich, 70-230 mesh, base A1203(Woelm, 5 g). The solvent was removed on a rotovap, and 60 A) leads to comparable results (see, also data in ref 7b,c).

5564 J. Am. Chem. SOC.,Vol. 114, No. 14, 1992 the dry powder was left at ambient temperature for an additional 10 min. Washing of the sorbent with ether gave 16a,bas a slightly yellow liquid (0.48 g, yield 89%, R f = 0.61, hexane-ether, 1:3, ratio a:b = 12:1, ‘H NMR). The ‘H NMR spectrum of the product is almost superimposable with that of the sample described above, the only difference being due to variation in the a:b ratio; MS (for the mixture) m/e 194 (M+). The product was immediately used in further reactions without any additional purification. 1-Metboxy-l-etbynyl-2-( 1’-hydroxyprop2’-en-l’-yl)cyclohexane(Aa) was prepared as was described for 10 from 16a,b (0.48 g, 2.5 mmol). The crude product (0.45 g, yield 87%) contained three stereoisomers in the ratio 9:1.6:1 (‘H NMR). Column chromatography on S i 0 2 (eluent hexane-ether, 25:l) gave 20a (0.33 g, yield 67%, R/ = 0.55, hexaneether, 3:l) as a colorless liquid: ’H NMR 5.81 (1 H, ddd, J = 17.3, 10.8, 5.0 Hz), 5.22 (1 H, dt, J = 17.3, 1.9 Hz), 5.05 (1 H, dt, J = 10.8, 1.9 Hz), 4.70 (1 H, m), 3.37 (3 H, s), 2.69 (1 H, s), 2.19 (1 H , m), 1.0-1.8 (8 H , m). Anal. Calcd for CI2Hl8O2:C, 74.19; H, 9.34. Found: C, 73.89; H, 9.20. 8-Hydroxy-2-methoxytricyclo[7.3.0.0z~7~odec-1( 12)-en-ll-one (21). Product 2Oa was converted into the respective C O ~ ( C Ocomplex )~ via a conventional treatment with C O ~ ( C O )Cyclization ~. of this complex (0.48 g, 1 mmol) under DSAC @io2, 55 OC, 4 H) gave the mixture of 2la and 21b in ca. 65% yield. PTLC afforded pure 21a (0.089 g, yield 40%, R, = 0.54, hexane-ether, 3:l) and 2lb (0.047 g, yield 21%. R, = 0.64, hexane-ether, 3:l) as colorless liquids. Similar cyclization (0.478 g, 1 mmol) under LPC (ether, 5 mL, 50 “C, 10 h, sealed vessel) gave a mixture of 2la,bin ca. 70% yield in the ratio 1:l. Pure 21a and 21b were isolated in 32% and 31% yields, respectively; MS (for both isomers) m / e 222 (M+), 190 (M+ - MeOH). For IH NMR data, see Tables 111 and IV. Anal. Calcd for CI3Hl8O3:C, 70.24; H, 8.16. Found: C, 70.03; H, 8.05 (214;C, 69.90; H, 7.95 (Zlb). Co,(CO), complex of l-methoxy-l-ethynyl-2-( 2’-metbyl-3’-chloro-l’oxopropy1)cyclobexane (23)was prepared as described for 3 from 6 (1.72 g, 4.4 mmol), 2-methyl-3-chloropropanoylfluoride (1.1 g, 10.9 mmol), and BF3 (490 mL, 19.5 mmol). After the removal of traces of the starting material, the crude product 23a-d (2.19 g, yield 94%, R/= 0.56, hexane-ether, 1O:l) was decomplexed into 24a-d. ’H NMR spectra of the latter revealed general patterns similar to those observed in 18a,band confirmed the presence of four components in the ratio 3:2:l:l; MS (for the mixture) m/e 243, 241 (M’), 228, 226 (M+ - Me), 212, 210 (M’ - MeO), 206 (M+ - Cl). No attempts were made to separate the isomers,and the mixture was immediately used for further transformations. 1-Methoxy-I-ethynyl-f-(2’-metbyll’-oxoprop-2’-enyl)cyclohexane (25a,b)was prepared by dehydrochlorination of the above mixture under the conditions described for 16a.b. Upon this treatment, 24a-d (0.97 g, 4 mmol) gave a mixture of stereoisomers 25a,b,which was separated by column chromatography on Si02 (hexane-ether, 401) into the individual isomers 25a (0.21 g, yield 25%, R/ = 0.22) and 25b (0.61 g, yield 74%, R/ = 0.26, hexane-ether, 1O:l); MS m / e (for both isomers) 206 (M*), 191 (M+ - Me), 174 (M+ - MeOH). 25a: IH NMR 5.91 (1 H, br s), 5.72 (1 H, br s), 3.30 (1 H, m), 3.28 (3 H, s), 2.61 (1 H, s), 2.23 (1 H, m), 1.85 (3 H, s), 1.1-1.8 (7 H, m); MS m/e 206 (M+), 191 (M+ - Me), 174 (M+ - MeOH). 25b ‘H NMR 5.89 (1 H, br s), 5.70 (1 H, br s), 3.64 (1 H, t, J = 5.2 Hz), 3.29 (3 H, s), 2.51 (1 H, s), 2.30 (1 H, m), 1.86 (3 H, s), 1.1-1.8 (7 H, m). Anal. Calcd for CI3Hl8O2:C, 75.69; H, 8.79. Found: C, 75.43; H, 8.65 (25a);C, 75.42; H, 8.70 (25b). l-Methoxy-l-ethynyl-2-( 1’-hydroxy-2’-methylprop2’-en-l’-yl)cyclohexane (26)was prepared as was described above for 10. Reduction of 25a (0.41 g, 2 mmol) gave a mixture of stereoisomers, which was separated by chromatography on S i 0 2 (hexane-ether, 30: l ) into individual 26a (0.08 g, yield 20%, R, = 0.34, hexane-ether, 3:l) and 26b (0.25 g, yield 60%, Rf= 0.25, hexane-ether, 3:l). Similarly, individual 26c (0.32 g, yield 60%, R/ = 0.27, hexane-ether, 3:l) and 266 (0.08 g, yield 15%, R/ = 0.40, hexane-ether, 3:l) were prepared starting from 25b (0.53 g, 2.6 mmol). Anal. Calcd for C13H2002: C, 74.96; H, 9.66. Found: C, 74.70; H, 9.58 (26b);C, 74.76; H, 9.53 (26c). 26a: ‘H NMR 4.86 (1 H, m), 4.84 (1 H, m),4.68 (1 H, br s), 3.38 (3 H, s), 2.71 (1 H, s), 1.67 (3 H, br s), 1.0-1.8 (9 H, m). 26b: ’ H NMR 4.86 (1 H, m), 4.83 (1 H, m), 4.28 (1 H, d, J = 9.6 Hz), 3.42 (3 H, s), 2.66 (1 H, s), 2.28 (1 H, m), 1.69 (3 H , br s), 1.0-1.8 (8 H, m). 26c: ‘ H N M R 4 . 8 9 ( l H , m ) , 4 . 8 2 ( 1 H , m ) , 4 . 3 8 ( 1 H , d , J = 8 . 8 H z ) , 3.37 (3 H, s), 2.64 (1 H, s), 1.68 (3 H, br s), 1.2-2.0 (9 H, m). 26d: ‘H NMR 5.06 (1 H, m). 4.90 (1 H, m), 4.81 (1 H, m), 3.35 (3 H , s), 2.57 (1 H , s), 2.29 (1 H, m), 1.66 (3 H , br s), 1.1-2.0 (8 H, m). 9-Methyl-8-hydroxy-2-methoxytricyclo[‘l,1 ( 12)-en1 1one (27). Alcohols 26a-cwere converted into their respective C O ~ ( C O ) ~ complexes, and the latter underwent IMPK cyclization under the conditions indicated below. Stereoisomers of the cyclized products were separated by PTLC (ether).

Gybin et al. 27a,b. From 26a (0.21 g, 1 mmol) under LPC (ether, 50 OC, 6 H), 27a (0.123 g, yield 52%, R/.= 0.48, ether) and 27b (0.016 g, yield 7% R, = 0.79, ether) were obtained. 2711:MS m / e 236 (M+); exact mass found 236.1416, C14H2003 requires 236.1412. 2% MS m / e 236 (M+), 221 (M+ - Me). 27c. From 26b (0.21 g, 1 mmol) under LPC (ether, 50 OC, 7 h), 27c (0.161 g, yield 68%, Rf = 0.67, ether) was obtained: MS m / e 236 (M’); exact mass found 236.1410, C14H2003 requires 236.1412. 27d,e. From 26c (0.21 g, 1 mmol) under LPC (ether, 60 OC, 8 H), 27d (0.1 11 g, yield 47%, R/ = 0.20, hexane-ether, 2:l) and 27e (0.016 g, yield 7%, Rf = 0.25, hexane-ether, 0.25) were obtained. A similar reaction under DSAC ( S O 2 , 70 OC, 10 h) gave the same products 27d and 27e in 53% and 5% yields, respectively. A major part of the 27d was isolated by the recrystallization from ether-pentane, 1:2. Separation of the mother liquor by PTLC gave additional amounts of 27d and 27e in admixture with 27d. 27d: mp 160-161 “C. Anal. Calcd for C14H2003: C, 71.16; H, 8.53. Found: C, 71.04; H, 8.52. 27e: MS m/e 236 (M+), 221 (M+ - Me). 27f. From 26d (0.21 g, 1 mmol) under LPC (ether-pentane, 1:1, 10 mL, 60 OC, 7 h), 27f (0.184 g, yield 78%, R/= 0.56, ether) was obtained. HRMS: calcd for CI4HZ0O3 236.1412, found 236.1408. For IH and ”C see Tables I11 and IV. NMR data of 27a,c,d,f, C O ~ ( C O )complex ~ of l-methoxy-l-etbynyl-2-[(E)-l’-oxobut-2’enyljcyclopentane (29)was prepared as described earlier for 3 from 28 (3.4 g, 9.0 mmol), crotonyl fluoride (1.47 g, 15 mmol), and BF, (650 mL, 26 mmol). After PTLC, 29 (2.60 g, yield 59%, R,.= 0.25, benzene) was isolated as a deep red liquid. The less polar fraction consisted of the Z isomer (0.43 g, yield 11%, Rr = 0.3, benzene). Its structure was ascertained by MS and ‘H NMR spectra of the decomplexed material. Only the E isomer of 29 was used for further conversions. Oxidative decomplexation of 29 gave (1R*,2S*)-l-methoxy-l-ethynyl-2-[(E)-l’-oxobut2’-enyl]cyclopentane (30) (yield 95%, mp 62-63 OC, pentane): MS m / e 192 (M+); exact mass found M+ 192.1 153, CI2Hl6O2requires 192.1 150; ‘H NMR 6.9 (1 H, dq, J = 16, 7 Hz), 6.55 (1 H, dq, J = 16, 1.5 Hz), 3.44 (1 H, t, J = 8 Hz), 3.28 (3 H, s), 2.68 (1 H, s), 1.9 (3 H, dd, J = 7, 1.5 Hz), 1.6-2.4 (6 H, m). The structure of 30 as the lR*,2S* isomer was unambiguously proven by X-ray data. l-Methoxy-l-ethynyl-2-[(E)-l’-hydroxybut-2’-enyl~yclopentane (31) was prepared as described above for 10. From 30 (0.15 g, 0.79 mmol), a mixture of 31a,b(0.143 g, yield 93%) was prepared. PTLC (column, hexane-ether, 2: 1) gave individual 31a (0.062 g, R, = 0.45, hexane-ether, 2:l) and 3lb (0.075 g, Rf= 0.39, hexane-ether, 2:l). 31a: ’H NMR 5.68 (1 H, dq, J = 16, 6.5 Hz), 5.50 (1 H, ddq, J = 16, 11, 1.6 Hz), 4.2 (1 H, t, J = 11 Hz), 3.36 (3 H, s), 2.61 (1 H, s), 1.66 (3 H, dd, J = 6.5, 1.6 Hz), 1.5-2.2 (7 H, m);MS m / z 194 (M’). 31b: ’ H N M R 5 . 6 7 ( 1 H , d q , J = 1 5 . 5 , 7 H z ) , 5 . 5 5 ( 1 H , d d q , J = 16, 3, 1.6 Hz),4.67 (1 H, br d, J = 11 Hz), 3.31 (3 H, s), 2.51 (1 H, s), 1.65 (3 H, dd, J = 7, 1.6 Hz), 1.6-2.3 (7 H, m); MS m / z 194 (M’). Attempted cyclization of Co-complexed 31a and 31b (SO2, 100 OC, 10 h, or hexane, 60 OC, 6 h, total conversion of the starting materials) did not produce even trace amounts of tricyclic products (MS data) and resulted in the formation of a mixture of no less than 4-5 products (TLC). l-Methoxy-l-ethynyl-2-[(E)-l’-methyl-l’-hydroxybut-2’-en-l’-yl]cyclopentane (32). A solution of MeMgI (8 mmol) in ether (10 mL) was added to 30 (0.585 g, 3.05 mmol) dissolved in ether (50 mL) at -55 OC. The reaction mixture was warmed up to -20 “ C and, after 20 min, quenched with NH4C1-H20. After the usual workup and solvent removal, a colorless oil was obtained (0.506 g, yield 80%, R, = 0.41, benzene-ether, lO:l), MS m / e 208 (M+). The attempt to separate the isomers by PTLC failed. The proposed structure as a 1,2-adduct is based on the appearance of the novel high-field Me signals (at 1.12 and 1.30) and on the similarity of the general ‘H NMR spectral pattern to those observed for 31a,b. The diastereoisomeric ratio was ca. 2:l (from the integration of nonoverlapping M e 0 signals). A mixture 32a,bwas converted into the respective Co complex, and the latter was applied to S O 2 and heated at 60 O C for 1 h. All starting material was consumed (TLC), but analysis of the reaction mixture revealed the presence of no less than five compounds (‘H NMR), none of them being a tricyclic product (MS). Co2(CO), Complex of l-Methoxy-l-ethynyl-2-(3’-chloropropionyl)cyclopentane (33). (i) Under Kinetically Controlled Conditions. Into a solution of 28 (3.4 g, 9.0 mmol) and 3-chloropropanoyl fluoride (0.88 g, 8 mmol) in CH2C12(80 mL) at -70 OC was introduced gaseous BFj (300 mL, 12 mmol) with a syringe. The mixture was kept for 20 min at -70 OC, quenched by cooled MeOH (4 mL), and then immediately neutralized by the addition of pyridine (0.96 g, 12 mmol). After the usual treatment and PTLC, unreacted 28 (0.48 g, yield 14%) and 33a,b (2.84 g, yield 63%, a:b = l : l . l , from ‘H NMR of the decomplexed sample) were recovered.

Stepwise AdE and Intramolecular Pauson-Khand Reactions (ii)Under Thermodynamically Controlled Conditions. The reaction was carried out as described above, the only difference being that prior to neutralization with pyridine the reaction mixture was kept at 20 "C for 30 min. The product was isolated in 60% yield and was shown to contain at least 95% ('H NMR) of a single isomer 33b: 'H NMR (for the decomplexed sample of 33b ) 3.66 (2 H, m), 2.9-3.4 (3 H, m), 3.28 (3 H, s), 2.68 (1 H, s), 1.6-2.4 (6 H , m). Adducts 33a,bwere immediately used without additional purification. l-Methoxy-l-ethynyl-2-( l'-oxoprop-2'-enyl)cyclopentane (34). Oxidative decomplexation with subsequent dehydrochlorination of 33b over A1203under the conditions described above for the preparation of 16a,b gave 34b as a single product, yield 85%: 'HNMR 6.82 (1 H, dd, J = 17.0, 10.5 Hz), 6.3 (1 H, dd, J = 17.0, 1.5 Hz), 5.7 (1 H , d d , J = 10.5, 1.5 Hz,) 3.36 (1 H, m), 3.28 (3 H , s), 2.68 (1 H, s), 1.6-2.4 (6 H , m); MS m / e 178 (M'). Anal. Calcd for CIIHI4O2:C, 74.13; H, 7.92. Found: C, 74.35; H, 8.15. Similarly, from a mixture 33a,b via oxidative decomplexation and dehydrochlorination, a mixture 34a,b was formed (yield 90% ratio a:b l:1.2, 'H NMR). The ' H NMR spectrum of this ketone reveals the presence (in addition to the aforementioned signals of 34b) the nonoverlapping signals of 34a: 6.6 (1 H, dd, J = 17, 10.5 Hz),6.2 (1 H, dd, J = 17, 1.5 Hz), 5.8 (1 H, dd, J = 10.5, 1.5 Hz), 3.40 (3 H, s), 2.54 (1 H, s); MS m / e 178 (M+). This mixture was used for further reactions without separation of the isomers. l-Methoxy-l-ethynyl-2-( 1'-hydroxyprop-2'-en-l'-yl)cyclopentane 35. Reduction of 34b under the conditions described above in the preparation of 10 gave a mixture of alcohols 35c,d (yield 95%, c:d = 1.5:1, Rf= 0.64 and 0.72, chloroform-ether, 4:1), which were separated by PTLC. 35c: 'H NMR 5.85 (1 H, ddd, J = 17.5, 10.5, 7.0 Hz), 5.25 (1 H,

J . Am. Chem. Soc., Vol. 114, No. 14, 1992

5565

preparation of 5. The residue was sealed and kept at 60 OC for 10 h. The resulting grayish powder was carefully washed with an EtOH-EtOAc mixture (30 mL, 1:5), and the solvent was removed. PTLC gave 40 (0.136 g, yield 27%), 41 (0.127 g, 23%), and 42 (0.020 g, yield 4%) as slightly colored liquids with Rf = 0.56, 0.10, and 0.42 (ether-hexane, 3:1), respectively. Similar products in the same ratio were formed by cyclization of 38 prepared from 25a,b. Thermolysis of 38 (0.49 g, 1 mmol) on Si02at 90 OC for 10 h gave, after similar treatment, 42 (0.1 g, yield 49%) and 40 (0.004 g, yield 2%) identical with the samples prepared above. 40: ' H NMR 5.73 ( 1 H, s), 2.44 and 2.27 (2 H, pair of AB doublets, J = 17.0 Hz), 2.18-2.45 (4 H, m), 1.5-1.9 (4 H, m), 1.3 (3 H, br s); I3C NMR 206.3 (C-1 l), 202.5 (C-8), 180.3 (C-1), 156.7 (C-2), 145.5 (C-7), 116.4(C-12), 54.5 (C-9),45.1 (C-10),27.1 (MeatC-9),23.8,21.1,20.9, 20.8 (C-3-C-6); MS m / e 202; exact mass found 202.0996, CI3Hl4O2 requires 202.0994. 41: 'H NMR 2.67 and 2.22 (pair of AA'BB', dd, J = 19.0, 1.9, 1.6 Hz), 2.51 and 2.31 (pair of AA'BB', dd, J = 19.3, 1.9, 1.6 Hz), 1.8-2.20 (4 H, m), 1.2-1.4 (4 H, m), 1.15 (3 H, br s); "C NMR 213.6 (C-11), 208.5 (C-8), 172.5 (C-2), 137.1 (C-7). 83.3 (C-l), 54.9 (C-9), 50.0 (C-12), 48.0 (C-lo), 19.2 (Meat C-9), 22.7, 21.8, 21.3, 19.7 (C-3-C-6); MS m / e 220; exact mass found 220.1106, CI3HI6O3 requires 220.1099. 42: 'H NMR 2.93 (1 H, m), 2.41 and 2.20 (pair of AA'BB', dd, J = 19.2, 1.8, 1.7 Hz), 2.67 and 2.18 (pair of AA'BB'X, ddd, J = 18.6, 1.8, 1.7, 3.6, 10.6 Hz),2.0-2.3 (4 H, m), 1.5-1.8 (4 H, m), 1.28 (3 H, br s); "C NMR 215.7 (C-ll), 210.3 (C-8), 172.6 (C-2), 137.3 (C-7), 50.6 (C-1), 50.5 (C-9), 47.70 (C-lo), 41.0 (C-12), 23.5 (Me at C-9), 26.6, 23.4, 22.2, 20.3 (C-3-C-6); MS 204; exact mass found 204.1 143, CI3Hl6O2requires 204.1 150. ~ of l-methoxy-l-ethynyl-2-(cyclopent-l'-enyl)dd,J=17.5,1.5Hz),5.07(1H,dd,J=10.5,1.5Hz),4.65(1H,m), C O ~ ( C O )complex cyclohexane (43)was prepared as described above for 3 from 6 (1.57 g, 3.31 (3 H, s), 1.4-2.1 (7 H, m); MS m / e 180 (M'). 35d: 'H NMR 5.81 4 mmol), 2 (0.5 g, 4.4 mmol), and BF3 (500 mL, 20 mmol) as a mixture (1 H , ddd, J = 17.0, 10, 5 Hz), 5.29 (1 H, dt, J = 17.0, 2 Hz), 5.07 (1 of cis and trans adducts 43a and 43b (1.87 g, 90% yield, R/= 0.66 and H, dt, J = 10.5, 2 Hz), 4.76 (1 H, m), 3.36 (3 H, s), 2.53 (1 H, s), 0.55, respectively, ether-hexane, 4:1, a:b = 2:l). A portion of this sample 1.6-2.21 (7 H, m); MS m / e 180 (M'). was separated into individual isomers by PTLC, and the latter were Both 35c and 3% were converted into respective Co complexes and decomplexed for the spectral identifications. subjected to the usual DSAC of the cyclization. No cyclic products were 43s (for the decomplexed sample): 'H NMR 6.73 (1 H, m), 3.31 (3 detected in the mixture of products formed after prolonged 1-5 h of H, s), 3.23 (1 H, dd, J = 10.2, 3.9 Hz), 2.56 (1 H, s), 2.2-2.6 (4 H, m), heating at 60 OC (MS data). 2.28 (1 H, m), 1.9 (2 H, m), 1.2-1.8 (7 H, m); MS m / e 232. 43b (for Reduction of the mixture 34a,b(0.257 g, 1.44 mmol) under the same the decomplexed sample): 'H NMR 6.73 (1 H, br s), 3.32 (3 H, s), 3.58 conditions gave a mixture of four isomeric alcohols 3Sa-d in 98% total (1 H, t , J = 5.0 Hz), 2.52 (1 H, s), 2.2-2.6 (4 H, m), 2.28 (1 H, m), 1.9 yield. PTLC allowed the isolation of pure 35a (0.089 g, yield 34% R/ (2 H, m), 1.2-1.8 (8 H, m); MS m / e 232. = 0.54, chloroform-ether, 4:1), 35d (0.055 g, yield 22% Rf = 0.64, chloroform-ether, 4:1), and 35c (0.090 g, yield 36%, R,.=0.72, chloroTetracyclo[l0.3.0.01.903.8lpentadeca-3(8),9-diene-2,lI-dione (44). form-ether, 4:l). 35,dwere identified by comparison (TLC, 'H NMR) Cyclization of the mixture of 43a,b(0.52 g, 1 mmol) was carried out on with the samples described above. No attempts were made to isolate pure Florisil (Fluka 5.2 g) at 85 "C for 12 h, as was described for the prepisomer 35b, identified by the presence of additional signals in the ' H aration of 40-42. After PTLC, 44 (0.121 g, yield 53%) was obtained as NMR spectrum of the initial mixture, ca. 3-5%. 3511:'H NMR 5.87 a colorless liquid (Rf=0.45, EtOAc-hexane, 1:l): 'H NMR 5.85 (1 H, (1 H, ddd, J = 17.5, 10.5, 5 Hz), 5.26 (1 H, dt, J = 17.5), 5.07 (1 H, s), 2.8 (1 H, d, J = 8.5 Hz), 2.5 and 2.25 (4 H, a pair of m), 1.6-2.0 (9 d t , J = 10.5, 2 Hz), 4.58 (1 H , m), 3.31 (3 H, s), 2.69 (1 H, s), 1.6-2.1 H, m), 1.3 ( 1 H, m); I3C NMR 209.5 (C-ll), 202.3 (C-2), 178.7 (C-9), (7 H, m). Anal. Calcd for CllH1602:C, 73.30; H, 8.95. Found: C, 157.5 (C-8), 147.6 (C-3), 117.5 (C-lo), 64.2 (C-l), 54.4 (C-12), 40.0, 73.01; H, 8.85. 30.3, 25.2, 24.0, 21.4 and 21.2 (C-13-'2-15, C-4-(2-7); IR 1705 (CO), 7-Hydroxy-2-methoxytricyc10[6.3.0.02~6]undec-1 I-en-IO-ones36. 35a 1611, 1594 cm-' (C=C). Anal. Calcd for CI5HI6O2:C, 78.92; H, 7.07. (0.089 g, 0.494 mmol) was converted into the respective Co complex by Found: C, 78.69; H, 7.22. The structure was established by X-ray treatment with C O ~ ( C O(0.186 )~ g, 0.543 mmol) in pentane (5 mL) at analysis. The same product 44 was formed in the trial experiments with 20 OC for 30 min. Then S i 0 2 (Silpearl, 1.78 g, water content ca. 15%) individual 43a and 43b. was added to the solution, the solvent which was removed in vacuo, and CO*(CO)~ complex of l-methoxy-l-ethynyl-2-( cyclopent-1'-en-1'-yljthe resulting powder was heated at 60 OC for 1 h. Washing with ether cyclopentane 46 was prepared as described above for 3 from 28 (0.76 g. and removal of the solvent gave 0.095 g of oily residue. FTLC separation 2 mmol), 1-cyclopentenoyl fluoride (0.24 g, 2.1 mmol), and BF3 (250 mL, gave 36a (0.038 g, yield 37%, R/ = 0.25, ether) and 36b (0.036 g, yield 10 mmol) as a mixture of trans and cis adducts 46a and 46b (0.98 g, 97% 35%, R/= 0.22, ether). For identification, both products were converted yield, Rf= 0.64 and 0.52, respectively, ether-hexane, 4:1, a:b = 1:3). For into the respective 7-acetoxy derivatives 37a (mp 93-95 "C, pentane) and the identification, a part of this sample was separated by PTLC into 37b (mp 90-91 OC, pentane), as was described above for the preparation individual 46a and 46b,and the latter were oxidatively decomplexed into of 11. the respective metal-free acyl methoxy adducts. 37a: ' H NMR 6.01 (1 H, d, J = 2.5 Hz, H - l l ) , 4.89 (1 H , d, J = 46s (for the decomplexed sample): ' H NMR 6.71 (1 H, br s), 3.29 5.5 Hz, H-7), 3.28 (1 H, d d d d , J = 7, 5.5, 3.5, 2.5 Hz, H-8), 3.19 (3 H, (3 H, s), 3.35 (1 H, m), 2.53 (1 H, s), 2.1-2.5 (4 H , m), 1.2-2.0 (8 H, s, MeO), 2.72 (1 H, t, J = 9 Hz, H-6), 2.46 (1 H, dd, J = 18.5, 7 Hz, m); MS m / e 218. 46b (for the decomplexed sample): 'HNMR 6.74 H-9), 2.28 (1 H, dd, J = 18.5, 3.5 Hz, H-9a), 2.01 (3 H, s, Ac), ( 1 H, br s), 3.32 (3 H, s), 3.22 (1 H, m), 2.57 (1 H, s), 2.2-2.5 (4 H, 1.45-2.25 (6 H , m). The structure was confirmed by X-ray analysis. m), 1.2-1.8 (8 H, m); MS m / e 218. Anal. Calcd for CI4Hl8O4:C, 67.18; H, 7.25. Found: C, 66.98; H, 7.15. 7-Methoxytetracyclo[9.3.0.0'~~~'ltetradec-8-ene-2,10-dione(47). The 3%: ' H NMR 6.07 (1 H, d, J = 2.5 Hz, H-11), 4.32 (1 H, dd, J = 9.5, above mixture 46a,b(1.01 g, 2 mmol) was dissolved in ether-pentane (20 7 Hz, H-7), 3.38 (1 H, dddd, J = 9.5, 6, 3, 2.5 Hz, H-8), 3.21 (3 H, S, mL, 1:l) and heated in a sealed vessel at 60 OC for 9 h. After removal MeO), 2.71 (1 H, m, H-6), 2.65 (1 H, dd, J = 19, 3 Hz, H-9), 2.51 (1 of the solvent, the dark red residue was separated by PTLC into two H, dd, J = 19, 6 Hz, H-9a). 2.08 (3 H, s, Ac), 1.35-2.1 (6 H, m). Anal. major components, namely, 46b,identical with material described above Calcd for CI4Hl8O4:C, 67.18; H, 7.25. Found: C, 66.80; H, 7.03. (0.66 g, 89% of the recovery for the initial convent of 46b),and tetra9-Methyltri~ycl~7,3.O.O~~~~odeca-l (12),2(7)-diene-8,ll-dione (40), cyclic adduct 47 (0.09 g, yield 19% or ca. 70% for the content of 4611) 9-Methyl-l-hydroxytri~yclo[7.3.O.~~~)dodec-2( 7)-ene8,1I-dione (41),and as colorless crystals: mp 63-65 OC (hexane); 'H NMR 6.03 (1 H, s), 9-Methyltricy~lo[7.3.O.O~~~~odec-2(7)-ene-8,1 1-dione(42). To the solu3.35 (3 H, s), 3.3 ( I H , m), 2.85 (1 H, m), 1.2-2.3 (12 H, m); the tion of 23 (1.32 g, 2.5 mmol) in pentane (25 mL) was added A1203 (Woelm, basic, 13.2 g, water content ca. 15%). The solvent was removed structure was established by X-ray analysis; MS m / e 246 (M'); exact mass found M+ 246.1250, CI5Hl8O3 requires 246.1256. on a rotovap, and oxygen was carefully stripped as described in the

5566

J. Am. Chem. SOC.1992, 114, 5566-5572

Recovered 46b (0.66g, 1.3 1 mmol) was dissolved in CH2C12(1 3 mL), cooled down to -70 'C, and treated with gaseous BF, (165 mL, 6.5 mmol). The mixture was kept at this temperature for 20 min and then quenched with MeOH (absolute, 2 mL). After the usual treatment the mixture 46a,b was isolated (0.56g, yield ca. 85%, a:b = 3:1) and identified by 'H NMR data comparison of the decomplexed material with

the abovementioned sample. Acknowledgment. This study is based on a project supported by the National Science Foundation, Grant No. 8921358. W.A.S. and R.C. are also indebted to CIES and the Fulbright Scholar Program. A.S.G. is grateful to the Soros Foundation.

The Enantioselective Synthesis of (-)-Physostigmine via Chiral Sulfoxides J. P.Marino,* S. Bogdan, and K. Kimura Contribution from the Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 481 09- 1055. Received December 23, 1991

Abstract: The total synthesisof naturally occurring (-)-physostigmine is described. The key element for the asymmetric induction is the chirality transfer from optically active 2-(alkylsulfinyl)indoles to indoline butyrolactones bearing two chiral centers. Novel features of this synthesis involve the use of a new class of sulfoxylating agents, N-(alkylsulfinyl)oxazolidinones, to prepare the starting indolyl sulfoxides and the correlation of the size of the alkyl group on the sulfoxide with the degree of asymmetric induction. The overall synthesis requires a dozen steps from commercially available 5-(benzy1oxy)indole.

Introduction A principal alkaloid of the Calabar bean, (-)-physostigmine (l),is a clinically useful anticholinesterase which has been used in the treatment of myasthenia gravis and glaucoma. More recently, analogues of (-)-physostigmine have also shown promise as therapeutic agents for Alzheimer's disease.'+2 The importance of this class of alkaloids has elicited a large amount of synthetic work toward the total synthesis of the naturally occurring (-)physostigmine. Earlier syntheses by and large produced only racemic phy~ostigmine.~In recent years, a number of enantiocontrolled syntheses have been reported4 for both the natural and unnatural physostigmine. Our interest in physostigmine emanated from the asymmetric synthesis of highly functionalized butyrolactones using chiral vinyl sulfoxides. In a previous communication,s we showed that 2-(methylsulfiny1)indole 3 could serve as a unique precursor for the physostigmine alkaloids via lactonization with dichloroketene (Scheme I). Moreover, recent reports from our group6 have established that the lactonization of chiral vinyl sulfoxides with dichloroketene occurs with complete control of the relative and absolute configuration. In this paper we want to summarize our earlier efforts toward racemic physostigmine and report a unique synthesis of optically active (-)-physostigmine, which involves the preparation of chiral indolyl sulfoxides and their use in the lactonization reaction.

Scheme I'

. Phb, 5

Me

PhkO, 5

'Reagents: (i) 1.2 equiv of BuLi, THF, -23 OC. (ii) 5 equiv of MeSOCl, THF, -23 OC. (iii) 5 equiv of Cl,CCOCl, 20 equiv of Zn(Cu), THF, 0 OC. (iv) 20 equiv of Al(Hg), THF/H20/MeOH (IO/ l/l),room temperature. (v) n-Bu,SnH, AIBN, benzene, 80 OC. (vi) Excess MeNH,, 10 equiv of 1 N HC1, anhydrous MeOH, -78 OC; cat. concentrated H2S04,DMF, 115 OC. (viii) Et3O+BFL,CH,CI,, room temperature, NaBH,, EtOH, 0 OC room temperature.

-

Scheme I1

MI

(1)Davis, K. L.; Mohs, R. C. Am. J . Psychiatry 1982, 139,1421. Beller, S. A.; Overall, J. E.; Swann, A. C. Psychopharmacology 1987, 87, 145. (2)Christie, J. E.; Shering, A.; Ferguson, J.; Glen, A. I. Br. J . Psychiatry 1981, 138,46. (3) For a review of synthetic approaches to the physostigmines, see: Takano, S.; Ogasawara, K. The Alkaloids; Brossi, A,, Ed.; Academic Press: San Diego, 1989;Vol. 36,pp 225-251. (4)(a) Takano, S.;Moriya, M.; Ogasawara, K. J . Org. Chem. 1991, 56, 5982-5984. (b) Node, M.; Hao, X.;Fuji, K. Chem. Lett. 1991, 57-60. (c) Lee, T.B. K.; Wong, G. S. K. J. Org. Chem. 1991,56,872-875.(d) Takano, S.;Sato, T.;Inomata, K.;Ogasawara, K. Heterocycles 1990, 31,411-414. (e) Takano, S.;Moriya, M.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109-1 12. (0 Yu, Q.; Brossi, A. Hererocycles 1988,27,745-750.(g) Takano, S.;Goto, E.; Himara, M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641-2643. (5)Marino, J. P.; Kim, M.-W.; Lawrence, R. J . Org. Chem. 1989, 54, 1 782-1 784. (6)(a) Marino, J. P.; Perez, A. D. J . Am. Chem. SOC. 1984, 106, 7643-7644. (b) Marino, J. P.; Fernandez de la Pradilla, R. Tetrahedron Lett. 1985, 26, 5382-5384. (c) Marino, J. P.; Fernandez de la Pradilla, R.; Laborde, E.Synthesis 1987, 1088-1091. (d) Marino, J. p.; Laborde, E.; Paley, R. J . Am. Chem. SOC.1988, 110,966-968.

.

P h b , Me 7

BnoO -

is Me 15

""&

__...___..__._

I( BHaTHF

181%)

+s 15

Me

H

Me

17

Scheme 111

Synthesis of Racemic Physostigmine Reaction of 5-(benzyloxy)indole (8) with ethylmagnesium bromide and methyl iodide afforded 5-(benzyloxy)-3-methylindole. Treatment with dimsyl sodium and tosyl chloride effected sulfonylation at the nitrogen. Deprotonation at the C-2 carbon (BuLi, -60 "C), followed by addition of dimethyl disulfide, produced the 2-(methylsulfenyl)indole derivative of 10. The racemic sulfoxide 12 was easily obtained by oxidation with m-CPBA (Scheme 11). The lactonization protocol calls for treatment of the vinyl sulfoxide

0002-7863/92/1514-5566$03.00/00 1992 American Chemical Society